The overall goal of this Program Project Application is to improve our understanding of the genetic and molecular control of bone remodeling in the context of aging by identifying a novel regulator, elucidating its modes of action and documenting its clinical importance. The four projects will examine (1) the role of brain-derived serotonin in the regulation of bone formation and its mechanisms of action (Karsenty); (2) the molecular mechanisms whereby gut-derived serotonin regulates osteoblast proliferation and bone formation (Kousteni); (3) the functional hierarchy between brain-derived and gut-derived serotonin as well as the therapeutic potential of inhibiting the synthesis of gut-derived serotonin; (4) the involvement of serotonin in depression-induced and gonadal-failure-induced osteoporosis in humans (Bilezikian). These projects will be supported by two essential cores. Core A is an administrative core integrating a biostatistical support, core B is a Bone Morphometry Core providing histomorphometry and microCT analyses. The coordination of the projects will be performed by the program director. This will be facilitated by the synergy and complementary between the projects, by our monthly meetings, by our interaction with the internal (monthly) and external (yearly) scientific advisory boards and by the supporting roles played by the cores. Together our studies should provide important and novel insights in the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging.